Formulations of oral gastrointestinal diagnostic X-ray contrast agents in combination with pharmaceutically acceptable clays

Abstract

Nanoparticulate crystalline substances formulated with stabilizers and pharmaceutically acceptable clays to enhance contact between the crystalline substances and the gastrointestinal tract. These formulations have improved safety profiles, a low potential for absorption, are not viscous and are not contraindicated for GI perforations or intestinal obstructions. The properties of the surfactant stabilizers are independent of the crystalline drug used and largely determine the extent to which the formulation coats the GI tract.

What is claimed is: 
     
       1. An orally/rectally administrable gastrointestinal diagnostic x-ray contrast formulation comprising: of from about 4 to about 45% w/v of an essentially water-insoluble particulate radiopaque crystalline material having an effective average particle size of less than about 2,000 nm;   of from about 0.5 to about 10% w/v of a bioadhesive surfactant stabilizer selected form the group consisting of: polyethylene-polypropylene glycol block polymers of the formula (i) (i) (polyethylene oxide) a  - (polypropylene oxide) b  - (polyethylene oxide) c  wherein a is 46, 52, 62, 75, 97, 98, 122 and 128;   b is 16, 30, 35, 39, 47, 54 and 67; and   c is 46, 52, 62, 75, 97, 98, 122 and 128;     (ii) polyvinyl alcohol,   (iii) polyvinyl pyrrolidone,   (iv) hydroxypropyl methylcellulose, and   (v) polyoxyethylene sorbitan mono-oleate;     from about 0.1 to 10% of a pharmaceutically acceptable clay selected from the group consisting of: montmorillonite, beidelite, nontronite, hectorite and saponite; and   water to make 100% w/v.   
     
     
       2. The orally/rectally administrable gastrointestinal diagnostic x-ray contrast formulation of claim 1 wherein said particulate radiopaque crystalline material is selected from the group consisting of: 3,5-Bis-acetylamino-2,4,6-triiodo-benzoic acid ethyl ester (WIN 05316), 2-(3,5-Bis-acetylamino-2,4,6-triiodo-benzyloxy)-2-methyl malonic acid (WIN 67975), Propanedioic Acid, [[3,5-bis-(acetylamino)-2,4,6-triiodo-benzoyl]oxy]-bis(1-methylethyl) ester acid ethyl ester (WIN 68165), Diethyl 5-acetylamino-2,4,6-triiodo-isophthalate (WIN 59316), Ethyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate (WIN 8883), Bis-[ 1-(ethoxycarbonyl)propyl]-2,4,6-triiodo-5-acetylamino-isophthalate (WIN 68183), 1,3,5-Triethyl-2,4,6-triiodobenzene (WIN 68756), 3,5-Bis-acetylamino-2,4,6-triiodo-benzoic acid 4-methoxy-benzyl ester (WIN 67754), 3,5-Bis-acetylamino-2,4,6-triiodo-benzoic acid 4-isopropyl benzoate ester (WIN 67956), (6-Ethoxy-6-oxohexyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate)(WIN 67722) and 3,5,-Bis-acetylamino-2,4,6-triiodo-benzoic acid 5-isopropoxycarbonyl-pentylester (WIN 67995). 
     
     
       3. The orally/rectally administrable gastrointestinal diagnostic x-ray contrast formulation of claim 1 wherein said particulate radiopaque crystalline material is selected from the group consisting of: barium sulfate, barium hexaborite, barium chromite, barium fluogallate, barium tri-ortho phosphate, barium metasilicate, barium titanate and barium zirconate. 
     
     
       4. The orally/rectally administrable gastrointestinal diagnostic x-ray contrast formulation of claim 1 further comprising up to 1% w/v of a secondary stabilizer selected from the group consisting of dioctylsulfosuccinate and sodium lauryl sulfate. 
     
     
       5. A method of carrying out x-ray examination of the gastrointestinal tract of a patient, said method comprises the oral/rectal administration to the patient an x-ray contrast composition comprising: of from about 4 to about 45% w/v of an essentially water-insoluble particulate radiopaque crystalline material having an effective average particle size of less than about 2,000 nm;   of from about 0.5 to about 10% w/v of a bioadhesive surfactant stabilizer selected form the group consisting of: polyethylene-polypropylene glycol block polymers of the formula (i) (i) (polyethylene oxide) a  - (Polypropylene oxide) b  - (Polyethylene oxide) c  wherein a is 46, 52, 62, 75, 97, 98, 122 and 128;   b is 16, 30, 35, 39, 47, 54 and 67; and   c is 46, 52, 62, 75, 97, 98, 122 and 128;     (ii) polyvinyl alcohol,   (iii) polyvinyl pyrrolidone,   (iv) hydroxypropyl methylcellulose, and   (v) polyoxyethylene sorbitan mono-oleate;     from about 0.1 to 10% of a pharmaceutically acceptable clay selected from the group consisting of: montmorillonite, beidelite, nontronite, hectorite and saponite; and   water to make 100% w/v.   
     
     
       6. The method of claim 5 wherein said particulate radiopaque crystalline material is selected from the group consisting of: 3,5-Bis-acetylamino-2,4,6-triiodo-benzoic acid ethyl ester (WIN 05316), 2-(3,5-Bis-acetylamino-2,4,6-triiodo-benzyloxy)-2-methyl malonic acid (WIN 67975), Propanedioic Acid, [[3,5-bis-(acetylamino)-2,4,6-triiodo-benzoyl]oxy]-bis(1-methylethyl) ester acid ethyl ester (WIN 68165), Diethyl 5-acetylamino-2,4,6-triiodo-isophthalate (WIN 59316), Ethyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate (WIN 8883), Bis-[1-(ethoxycarbonyl)propyl]-2,4,6-triiodo-5-acetylamino-isophthalate (WIN 68183), 1,3,5-Triethyl-2,4,6-triiodobenzene (WIN 68756), 3,5-Bis-acetylamino-2,4,6-triiodo-benzoic acid 4-methoxy-benzyl ester (WIN 67754), 3,5-Bis-acetylamino-2,4,6-triiodo-benzoic acid 4-isopropyl benzoate ester (WIN 67956), (6-Ethoxy-6-oxohexyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate) (WIN 67722) and 3,5,-Bis-acetylamino-2,4,6-triiodo-benzoic acid 5-isopropoxycarbonyl-pentylester (WIN 67995). 
     
     
       7. The method of claim 5 wherein said particulate radiopaque crystalline material is selected from the group consisting of: barium sulfate, barium hexaborite, barium chromite, barium fluogallate, barium tri-ortho phosphate, barium metasilicate, barium titanate and barium zirconate. 
     
     
       8. The method of claim 5 wherein said composition further comprises up to 1% w/v of a secondary stabilizer selected from the group consisting of dioctylsulfosuccinate and sodium lauryl sulfate.